DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim Status
Pending claims 1-3 and 7-33 have been examined on the merits. Claims 24-33 were newly added claims.
Withdrawn Grounds of Rejection
The rejection of claims 1, 3 and 7-23 under 35 U.S.C. 103 as being unpatentable over Jonas (US PG-PUB 2010/0173994) in view of Gold et al. (Diabetologia) 2007 Apr;50(4):711-9 and Squitti et. al., J. Alzheimer’s Dis. 2017; 56(3):1055-1064, Cooper et al. (Drugs) 2011 Jul 9; 71(10):1281-320, is withdrawn due to the claim amendments and the newly added claims.
The rejection of Claims 1-3 and 7-23 under 35 U.S.C. 112(a) is withdrawn due to the claim amendments and cancellation. Therefore, Applicant’s argument directed specifically to this rejection have not been further addressed.
The rejection of claims 1, 3, 7- 8, 10, 14- 20 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-6, 26, 29, 40, 44-46 of U.S. Patent No. 7,928,094 in view of Jonas (US PG-PUB 2010/0173994), Gold et al. (Diabetologia) 2007 Apr; 50(4):711-9 and Squitti et. al., J. Alzheimer’s Dis. 2017; 56(3):1055-1064, is withdrawn because Applicant’s arguments are persuasive.
The rejection of claims 1, 3- 8, 10, 14- 20 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1- 2, 4- 9 of U.S. Patent No. 11,419,831 in view of Jonas (US PG-PUB 2010/0173994), Gold et al. (Diabetologia) 2007 Apr; 50(4):711-9 and Squitti et. al., J. Alzheimer’s Dis. 2017; 56(3):1055-1064 is withdrawn because Applicant’s arguments are persuasive.
The rejection of claims 1, 3- 8, 10, 14- 20 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1- 2, 4- 9 of U.S. Patent No. 11,419,831 in view of Jonas (US PG-PUB 2010/0173994), Gold et al. (Diabetologia) 2007 Apr; 50(4):711-9 and Squitti et. al., J. Alzheimer’s Dis. 2017; 56(3):1055-1064 is withdrawn because Applicant’s arguments are persuasive.
Claim interpretation
The claimed invention describes “wherein elevated brain hippocampal copper in said subject is reduced or normalized.” In accordance with the specification (page 13 and 31) “Reductions in total copper or copper values in a subject lead to and are surrogates for reductions in hippocampal copper.” “In some embodiments, excess copper in a subject can be measured by methods such as mass spectrometry of a tissue sample, CSP (cerebral spinal fluid) aspirate, and/or urine copper output. In some embodiments, treating copper excess can be measured by the slowing or reversing of the shrinkage of the hippocampus by known imaging methods (e.g. MRI - magnetic resonance imaging) of a subject undergoing treatment. Therefore, the claim limitation requires that elevated copper associated with the brain hippocampus be reduced or normalized but does not explicitly require direct in vivo quantification of copper within hippocampal tissue. In particular, the limitation does not require (1) direct sampling or biopsy of hippocampal tissue, (2) direct measurement of copper concentration in the hippocampus, (3) use of any analytical, imaging, MRI, PET, or copper-specific detection technique to measure copper concentration in the hippocampus, but rather assessing physical changes, including brain volume. Thus, the claimed reduction or normalization of elevated hippocampal copper may be evaluated indirectly using systemic copper measurement and/or imaging of the hippocampus, rather than by directly sampling and measuring copper in the hippocampus.
New Grounds of Rejection due to the Claim Amendments and newly added claims
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 3, and 7-33 are rejected under 35 U.S.C. 103 as being unpatentable over Jonas (US PG-PUB 2010/0173994) in view of Gold et al. (Diabetologia) 2007 Apr;50(4):711-9, Squitti et. al., J Alzheimer’s Dis. 2017; 56(3):1055-1064, Cooper et al. (Drugs) 2011 Jul 9; 71(10):1281-320, Hermann W. Ann Transl. Med. 2019 Apr; 7(Suppl 2):S63. As evidence by Philbert et al., EBioMedicine. 2022 Dec;86:104317.
Regarding claims 1, 14, 26, and 28, Jonas (paragraphs [0027]-[0030], [0178], [0189], [0192]) teaches a pharmaceutical composition comprising triethylenetetramine compounds, including but not limited triethylenetetramine disuccinate, to treat a human subject with undesired copper levels, including those with type 2 diabetes. (e.g., paragraphs [0179], [0191]-[0193]). Regarding suitable dosages, Jonas (page 13, [0181] bridged page 14) teaches that triethylenetetramine compounds, including triethylenetetramine disuccinate (i.e., “…the daily dosage level of the compounds herein…”, can be administered orally within the range from about 1 mg to about 2400 mg per day (in single or divided doses). Jonas (paragraphs [0004], [0011], [0191]-[0192]) teaches that triethylenetetramine compounds are useful for copper-related neurogenerative disease including Alzheimer’s, Parkinson’s, and Wilson’s disease. Given that Wilson’s disease is characterize by pathological copper accumulation that also involve the brain , and triethylenetetramine (trientine) promotes its urinary excretion; thus, a person of ordinary skill in the art (POSITA) would reasonably infer and a expect triethylenetetramine-mediated mobilization of excess copper from the brain/CNS into circulation, where the copper would be chelated and subsequently eliminated though the urine.
Jonas, however, does not explicitly teach triethylenetetramine compounds are capable of reducing elevated hippocampal copper levels.
Cooper (page 1282) teaches that type 2 diabetes (T2DM) is associated with systemic copper overload and that Trientine (TETA) was administered to diabetic subjects to prevent or reverse diabetic copper overload. Cooper (page 1282) also discloses that TETA acts as a highly selective copper chelator and extracts excess systemic copper into the urine, thereby reducing copper overload. Cooper (page 1282) discloses that TETA had also been used as a second-line treatment for Wilson’s disease. Therefore, Copper provides a known therapeutic regimen by which excess systemic copper can be chelated and eliminated through urine excretion. Furthermore, cooper (page 1284 and 1309) also discloses the role of copper in the brain and copper-mediated oxidative stress in cerebral vascular tissues in connection with Alzheimer’s disease and vascular dementia. Cooper (page 1309) further discloses patients with Alzheimer’s disease and vascular dementia patients who also manifest T2DM will presumably exhibit copper overload. Therefore, a POSITA would have reasonably understood that administration of triethylenetetramine would reduce the systemic burden of excess copper by chelation and urinary excretion. Therefore, a POSITA would also recognize that TETA-mediated copper chelation could reduce the systemic excess copper in diabetic patients.
Squitti (page 1055-1056 and 1060-1061) teaches that patients with type2 diabetes exhibit elevated of free copper, which drives the disease progression; thus, motivating copper-lowering therapy as discussed by Jonas. As evidence by Philbert (page 1 and 8) disclosing that type 2 diabetes can be associated with elevated hippocampal copper, and that elevated copper levels were present in the T2DM hippocampus, approaching those reported in untreated cerebral Wilson’s disease, suggests that copper-lowering therapies to those used for WD can also have therapeutic application in type diabetes. Therefore, it would have been obvious to a POSITA to modify Jonas’ teachings in view of Squitti’s disclosure to arrive at the claimed invention, a therapeutic approach of chelating copper type II diabetes. Furthermore, regardless of where copper is accumulated, triethylenetetramine compounds such as triethylenetetramine disuccinate, are well-known selective copper chelators that systemically removes excess copper Wilson’s, Alzheimer’s, and Parkinson’s disease (the brain). Therefore, a POSITA would recognize that administering triethylenetetramine disuccinate naturally encompassing the brain including hippocampus, as it is the earliest-affected brain region in type 2 diabetes, as disclosed by Gold (page 711-712 and 716-718). Therefore, a POSITA would reasonably expect that an agent known to remove excess copper necessarily implies reduction in copper levels. It is also important to note, reducing or normalizing copper levels would have been an expected result of administering the copper-chelating agent to a subject having elevated copper. Furthermore, the limitation that “elevated brain hippocampal copper” is reduced or normalized does not render the claim patentable because it expresses the intended biological result or mechanism of administering the known copper-chelating agent to a subject. For this reason, the instant claims are an obvious routine extension of the combined teachings of Jonas, Gold and Squitti, because the systemic distribution of copper removal inherently encompasses chelating any excess copper in the body or reduces copper levels, including the brain.
Regarding claim 3, Jonas, as applied to claim 1 above, (page 4, [0046]; page 15, [0195]) teaches a pharmaceutical composition comprising triethylenetetramine compounds and one or more pharmaceutically acceptable excipients or carriers; which can be a delayed release composition.
Regarding claims 7-8, Jonas (page 3) teaches polymorphs of various triethylenetetramine salts, including triethylenetetramine disuccinate, triethylenetetramine tetrahydrochloride, and triethylenetetramine Dihydrochloride, and also discloses the crystalline forms of triethylenetetramine disuccinate anhydrate.
Regarding claim 9, Jonas teaches about Alzheimer’s but does not explicitly use the term subject ‘shows signs of cerebral degeneration.’
However, Cooper at page 1309 discloses that diabetic patients with cerebrovascular disorders might exhibit signs of cerebral degeneration. This is because, Cooper at page 1309 discloses that defective copper regulation and oxidative stress in cerebral vessels in Alzheimer and vascular dementia patients with type 2 diabetes show copper overload, suggesting a shared pathological mechanism involving cerebrovascular damage. Given the association of diabetes with vascular complication, particularly in the brain, it is reasonable for one of ordinary skill in the art to consider diabetic patients with affected cerebral vessels could potentially experience degeneration as a result of these vascular and metabolic disorder. Given this, it would have been obvious to one of ordinary skill in the art to consider combining the teachings of Jonas and Cooper and could expect triethylenetetramine compounds to similarly improve signs of cerebral degeneration by reducing copper levels, as also observed with patients with Wilson’s disease.
Regarding claim 10, Jonas (page 14) teaches that the pharmaceutical composition is applicable for cognitive impairment like Alzheimer’s disease. Therefore, a method of treating Alzheimer’s inherently includes cognitive decline and dementia.
Regarding claim 11, Jonas does not explicitly teach diminished spatial memory or ability to remember directions, locations, and orientation.
However, Gold (page 712) teaches that type 2 diabetes is associated with cognitive impairment, including reduction in cognitive functioning and brain damage or atrophy. Gold (page 712 and 716) teaches that type 2 diabetes causes brain damage and lowers memory performance, which may result in a decline of spatial memory and orientation. Given that improvement in diabetes control is linked to better cognitive function, it would be obvious to one of ordinary skill in the art to consider combining the teachings of Jonas and Gold in treating diminished spatial memory in patient with diabetes with triethylenetetramine compounds and arrive at the claim invention.
Regarding claim 12- 13, Jonas teaches (page 15) teaches the use of triethylenetetramine disuccinate anhydrate with an additional hypoglycemic agent, such as metformin, a biguanide, to treat type 2 diabetes.
Regarding claim 15, Jonas (page 15) teaches pharmaceutical compositions, including tablets, capsules and other oral delivery forms and formulations.
Regarding claims 16-17 and 19, Jonas (page 13-14) teaches that triethylenetetramine compounds, including salts like triethylenetetramine dihydrochloride and triethylenetetramine disuccinate, may be administered within the range of about 1 mg to about 2400 mg per day (in single or divided doses). While Jonas does not explicitly mention BID, TID or QID, however, it is known in the that art that “divided dose prescription” refers to splitting a medication’s total daily amount into multiple, smaller doses to be taken throughout the day, which commonly means BID, TID or QID administration.
Regarding claim 18 and 20, Jonas at page 13- 14 teaches that triethylenetetramine compounds, including salts like triethylenetetramine disuccinate, may be administered within the range of 1 mg to 2400 mg per day (in single or divided doses). Jonas does not teach triethylenetetramine disuccinate in an amount of about 2800 mg daily or divided dose. However, an increase from 2400 to 2800 mg is a routine optimization effort to enhance therapeutic effectiveness. Therefore, such adjustment falls within standard pharmaceutical practice and does not reflect inventive step. In addition, “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” See MPEP 2141(11).
Regarding claim 21-25, and as applied to claims 1, and 7-8 above, those claims require a pharmaceutical composition comprising one of the three compounds. This requirement is met because Jonas ([0206]) teaches the following:
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The instruction for use of the compound is not considered a limitation as it is not functionally related; thus, the instruction is granted little patentable weight. See MPEP 2112.01
Regarding Claims 27 and 29-31, and as applied to claims 1, 14, 26, and 28 above, Cooper (page 1282, 1286, 1299, 1309, and 1311) discloses that triethylenetetramine disuccinate as a useful therapeutic agent for both diabetes and neurodegenerative disorders, including Alzheimer’s disease, and further characterizes these conditions as involving copper-related tissue damage and dysregulated copper metabolism rather than uniform copper deficiency. Furthermore, Hermann (page 3) teaches ranges for copper metabolism in adults, with normal serum copper concentration of about 79–131 mg/dL in men and 74–122 mg/dL in women and identifies free serum copper of less than <10 mg/dL as a standard reference value. Herman also identifies normal urine copper as less than <65 mg/day. Therefore, these values would have provided a POSITA with reference point for determining whether copper levels, by monitoring copper in urine as an example, had been reduced toward a normal physiological range during copper-chelation therapy. Moreover, selecting a serum free copper threshold of about 10ug/dL for identifying elevated copper status would have been an obvious selection of a known clinical parameter for evaluating copper status, and arrive at the claimed invention.
Regarding claims 32-33, and as applied to claim 1, 14 and 26, 28 above, Gold (page 712-713 and 716) discloses magnetic resonance imaging as a useful diagnostic technique to measure hippocampal damage associated with diabetes-related memory impairment. Therefore, given the known association between elevated copper and cognitive impairment, a POSITA would have been motivated with reasonable expectation of success to use MRI to evaluate hippocampal changes before and after copper-lowering treatment.
Response to Arguments
Claim Rejections -35 USC §103
Applicant argues that claim 2 was previously indicated as free of the art. Applicant subsequently cancelled claim 2 and incorporated the limitation into claim 1, as a result claim 1 is now free of the art and a Notice of Allowance is warranted. Applicant’s argument is not persuasive. The incorporation of a limitation previously recited in a dependent claim into claim1 does not, by itself, establish that the resulting amended claim is allowable. Keep in mind that the amendment permits the Examiner to reassess the patentability of the amended claim, including the newly incorporated limitation. Therefore, the Examiner has properly reconsidered amended claim 1 in view of the amendment and the prior art of record, and has issued new grounds of rejection in view of the claim amendment and the newly added claims. Furthermore, the kit claims are also rejected for the same reasons applicable to the corresponding methods claims, including the rejection of claim 1. Thus, the kit claims remain rejected for the same reason set forth above.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/P.P.E./
Examiner, Art Unit 1622
/JAMES H ALSTRUM-ACEVEDO/Supervisory Patent Examiner, Art Unit 1622
